The incidence of obesity has reached epidemic proportions, is a major health burden, and costs the U.S. billions of dollars in health care and lost productivity. Failure to develop effective treatments for obesity is in large part due to a lack of clear understanding as to how food intake and energy balance are regulated by the CNS. Thus, research to determine the processes by which food intake and energy balance are controlled is likely to have a major impact on public health, but the research to date has been imbalanced. For whereas considerable effort has been devoted to understanding the neurochemical response to negative energy balance, relatively little attention has been devoted to the inverse situation of positive energy balance. This oversight is significant since obesity is necessarily associated with periods of positive energy balance and therefore can be considered as a failure of the body weight regulatory system to respond appropriately to positive energy balance. Thus studying the responses to positive energy balance may provide valuable clues concerning the etiology of obesity. Moreover, the regulatory responses to positive energy balance represent the recruitment of endogenous systems that produce reduced food intake, increased energy expenditure and significant weight loss. Finding potential ways to mimic or trigger these endogenous regulatory response systems could provide unique insights and therapeutic strategies for the treatment of obesity. The current proposal seeks to identify critical aspects of this response system. When animals are force-fed calories in excess of caloric need (involuntary overfeeding), their spontaneous food intake drops to near zero and they gain body weight. Additionally, for some time after the overfeeding regimen is terminated, spontaneous food intake remains low until body weight has returned to control levels. Our data indicate that this regulatory response to positive energy balance is mediated by the CNS melanocortin system. We propose assessing several hypotheses concerning how the CNS melanocortin system orchestrates the response to positive energy balance. First, we will determine the critical population of melanocortin receptors that mediate the reduced food intake and increased energy expenditure that follow a period of positive energy balance. Second, we will determine the critical inputs into the melanocortin system that signal positive energy balance. Finally, we will evaluate the unique effects of an endogenous melanocortin receptor antagonist that counteracts the normal response to positive energy balance. The information from this proposal will be critical to a complete picture of how energy balance is regulated and how disorders of energy balance such as obesity may be treated.